G Progressive degradation of endoplasmic reticulum (ER). (b) Beta-cells in diabetic female NOD mouse (40-week old, 4-h fasting BG: 559 mg/dL) appears to be intact despite the presence of ongoing insulitis. (a) Non-diabetic male NOD mouse (41-week old, 4-h fasting BG: 136 mg/dL) showing a hyperactive beta-cell with lymphocyte infiltration and vesicles without dense core granules. F Ultrastructural analysis of hypertrophic islets in non-diabetic and diabetic littermates.
c A serial section stained for CD8-positive lymphocytes. (b) A serial section stained for CD4-positive lymphocytes by ABC-staining (brown). (a) Hematoxylin-Eosin (HE) staining of the islet showing peripheral- and intra-islet infiltrating lymphocytes and remaining endocrine islet cells. E Hypertrophic islet with massive infiltration of T-lymphocytes. Insulin (green), glucagon (red), somatostatin (white) and nuclei (blue). C Intraislet capillary network in the body region of a wild-type mouse at 21-week. Note that substantial beta-cell destruction is observed in the NOD pancreas (i.e. B The body region of the NOD mouse shown in A. A Visualization of spatial islet distribution in the context of the vascular network in the intact pancreas. 1 Immune cell infiltration and beta-cell destruction in prediabetic NOD mice. Together these findings highlight the strength of the unique approach of comparing progressor and non-progressor NOD mice to identify metabolic perturbations involved in T1D progression.įig. Key T1D-associated perturbations were related with: (1) increased plasma glucose and reduced 1,5-anhydroglucitol markers of glycemic control (2) increased allantoin, gluconic acid and nitric acid-derived saccharic acid markers of oxidative stress (3) reduced lysine, an insulin secretagogue (4) increased branched-chain amino acids, isoleucine and valine (5) reduced unsaturated fatty acids including arachidonic acid and (6) perturbations in urea cycle intermediates suggesting increased arginine-dependent NO synthesis. Gas chromatography time of flight mass spectrometry was used to measure >470 circulating metabolites in male and female progressor and non-progressor animals (n = 76) across a wide range of ages (neonates to >40-week). Statistical and multivariate analyses were used to identify age and sex independent metabolic markers which best differentiated progressor and non-progressor animals’ metabolic profiles. While both progressor and non-progressor animals displayed lymphocyte infiltration and endoplasmic reticulum stress in the pancreas tissue, overt T1D did not develop until animals lost ~70 % of the total beta-cell mass. Total beta-cell mass was quantified in the intact pancreas using transgenic NOD mice expressing green fluorescent protein under the control of mouse insulin I promoter. This study examined the circulating metabolomic profiles of NOD mice progressing or not progressing to T1D. However, not all animals develop overt diabetes. Non-obese diabetic (NOD) mice are a widely-used model of type 1 diabetes (T1D).
You can check out the full paper, 10.1007/s1130-2, or take a look at the abstract and figures below. Recently I was lucky enough to publish some of my research findings in the Journal Metabolomics. Diabetes associated metabolomic perturbations in NOD mice